Phytotherapy for benign prostatic hyperplasia - Graminex
Phytotherapy for benign prostatic hyperplasia - Graminex
Phytotherapy for benign prostatic hyperplasia - Graminex
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P R O S T A T E S U P P O R T :<br />
GRAMINEX Flower Pollen Extract<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
Timothy J Wilt*, Areef Ishani, Indulis Rutks and Roderick MacDonald<br />
Minneapolis VA Center <strong>for</strong> Chronic Diseases Outcomes Research, 1 Veterans Drive (111-0),<br />
Minneapolis, MN 55417, USA<br />
Abstract<br />
Objective<br />
To systematically review the existing evidence regarding the efficacy and safety of phytotherapeutic<br />
compounds used to treat men with symptomatic <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong> (BPH).<br />
Design<br />
Randomized trials were identified searching MEDLINE (1966±1997), EMBASE Phytodok, the Cochrane<br />
Library, bibliographies of identified trials and review articles, and contact with relevant authors and drug<br />
companies. The studies were included if men had symptomatic <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong>, the<br />
intervention was a phytotherapeutic reparational one or combined, a control group received placebo or<br />
other pharmacologic therapies <strong>for</strong> BPH, and the treatment duration was at least 30 days. Key data were<br />
extracted independently by two investigators.<br />
Results<br />
A total of 44 studies of six phytotherapeutic agents (Serenoa repens, Hypoxis rooperi, Secale cereale,<br />
Pygeum africanum, Urtica dioica, Curcubita pepo) met inclusion criteria and were reviewed. Many studies<br />
did not report results in a method allowing meta-analysis. Serenoa repens, extracted from the saw<br />
palmetto, is the most widely used phytotherapeutic agent <strong>for</strong> BPH. A total of 18 trials involving 2939 men<br />
were reviewed. Compared with men receiving placebo, men taking Serenoa repens reported greater<br />
improvement of urinary tract symptoms and flow measures. Serenoa repens decreased nocturia<br />
(weighted mean difference .WMD. 20:76 times per evening; 95% CI . 21:22 to 20.32; n . 10 studies) and<br />
improved peak urine flow.WMD . 1:93 ml s21; 95% CI . 0:72 to 3.14, n . 8 studies). Men treated with<br />
Serenoa repens rated greater improvement of their urinary tract symptoms versus men taking placebo<br />
(risk ratio of improvement. 1:72; 95% CI . 1:21 to 2.44, n . 8 studies). Improvement in symptoms of BPH<br />
was comparable to men receiving the finasteride. Hypoxis rooperi (n . 4 studies, 519 men) was also<br />
demonstrated to be effective in improving symptom scores and flow measures compared with placebo.<br />
For the two studies reporting the International Prostate Symptom Score, the WMD was 24.9 IPSS points<br />
(95% CI . 26:3 to 23.5, n . 2 studies) and the WMD <strong>for</strong> peak urine flow was 3.91 ml s21 (95% CI . 0:91 to<br />
6.90, n . 4 studies). Secale cereale (n . 4 studies, 444 men) was found to modestly improve overall<br />
urological symptoms. Pygeum africanum (n . 17 studies, 900 men) may be a useful treatment option <strong>for</strong><br />
BPH. However, review of the literature has found inadequate reporting of outcomes which currently limit<br />
the ability to estimate its safety and efficacy. The studies involving Urtica dioica and Curcubita pepo are<br />
limited although these agents may be effective combined with other plant extracts such as Serenoa and<br />
Pygeum. Adverse events due to phytotherapies were reported to be generally mild and infrequent.<br />
Conclusions<br />
Randomized studies of Serenoa repens, alone or in combination with other plant extracts, have provided<br />
the strongest evidence <strong>for</strong> efficacy and tolerability in treatment of BPH in comparison with other<br />
phytotherapies. Serenoa repens appears to be a useful option <strong>for</strong> improving lower urinary tract symptoms<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
1 | P a g e
and flow measures. Hypoxis rooperi and Secale cereal also appear to improve BPH symptoms although<br />
the evidence is less strong <strong>for</strong> these products. Pygeum africanum has been studied extensively but<br />
inadequate reporting of outcomes limits the ability to conclusively recommend it. There is no convincing<br />
evidence supporting the use of Urtica dioica or Curcubita pepo alone <strong>for</strong> treatment of BPH. Overall,<br />
phytotherapies are less costly, well tolerated and adverse events are generally mild and infrequent.<br />
Future randomized controlled trials using standardized preparations of phytotherapeutic agents with<br />
longer study durations are needed to determine their long-term effectiveness in the treatment of BPH.<br />
Keywords: <strong>Phytotherapy</strong>, Benign <strong>prostatic</strong> <strong>hyperplasia</strong>, Randomized controlled trials, Systematic reviews, Meta-analysis, Public<br />
health nutrition: 3(4a), 459±472 459<br />
<strong>Phytotherapy</strong> or the use of plant extracts <strong>for</strong><br />
treatment of lower urinary tract symptoms<br />
(LUTS) consistent with <strong>benign</strong> <strong>prostatic</strong><br />
<strong>hyperplasia</strong> (BPH) was first described in Egypt<br />
in the 15th century BC1. <strong>Phytotherapy</strong> is<br />
common in Europe and is increasing in the<br />
Western Hemisphere. In 1998, the sale of<br />
botanical medications in the United States was<br />
$1.5 billion per year and the use of<br />
phytotherapeutic compounds increased nearly<br />
70% among US adults 2,3. About 30<br />
phytotherapeutic compounds are used <strong>for</strong> the<br />
treatment of BPH (Table 1). Phytotherapeutic<br />
agents represent nearly half the medications<br />
dispensed <strong>for</strong> treatment of BPH in Italy,<br />
compared with 5% <strong>for</strong> alpha-blockers and 5% <strong>for</strong><br />
5a-reductase inhibitors 4. In Germany and<br />
Austria, phytotherapy is the first-line treatment<br />
<strong>for</strong> mild to moderate lower urinary tract<br />
symptoms and represents more than 90% of<br />
drugs prescribed <strong>for</strong> treatment of BPH. In the<br />
United States, phytotherapies <strong>for</strong> BPH are<br />
available as nonprescription dietary<br />
supplements. Nearly a quarter of men attending<br />
a United States urology clinic who had<br />
previously treated BPH indicated they had used<br />
phytotherapeutic agents <strong>for</strong> self-treatment of<br />
urinary tract symptoms 5.<br />
Phytotherapies are often promoted to ‘maintain<br />
a healthy prostate’ and as natural and harmless<br />
treatment of BPH symptoms. Despite their<br />
popularity with the public there has been<br />
reluctance among many practitioners to routinely<br />
recommend these products. This is because of<br />
uncertainty regarding their efficacy and safety<br />
6,7. Most phytotherapeutic compounds are<br />
unlicensed and do not require evidence of<br />
efficacy, safety or purity. There have been over<br />
40 published randomized controlled trials<br />
evaluating the efficacy of phytotherapy <strong>for</strong><br />
symptomatic BPH in approximately 5000 men.<br />
Many more trials are in progress and should<br />
provide needed evidence regarding the role of<br />
phytotherapeutic products.<br />
Systematic reviews of the existing literature<br />
provide a systematic assembly of the results of<br />
primary investigations using strategies that limit<br />
bias and random error 8. Systematic reviews<br />
efficiently integrate unmanageable amounts of<br />
in<strong>for</strong>mation and provide results that allow <strong>for</strong><br />
rational decision making. They can establish<br />
whether findings are consistent and generalized<br />
or whether findings vary by subsets. If clinically<br />
and statistically appropriate, a quantitative<br />
summary (meta-analysis) can be per<strong>for</strong>med<br />
resulting in statistical pooling of results and<br />
enhancement of the estimates of therapeutic<br />
effects and risk estimates. This is especially<br />
helpful when a large number of small trials have<br />
been conducted or when results from<br />
comparable studies provide differing results.<br />
Systematic reviews also identify gaps in existing<br />
evidence and make recommendations <strong>for</strong> future<br />
research to close these scientific and clinical<br />
gaps. Phytotherapeutic compounds Serenoa<br />
repens (saw palmetto) background the most<br />
widely used phytotherapeutic agent <strong>for</strong> BPH is<br />
the extract of the dried ripe fruit from the<br />
American dwarf palm plant, saw palmetto,<br />
Serenoa repens (also known by its botanical<br />
name as Sabal serrulata). Serenoa repens has<br />
been approved in France and Germany <strong>for</strong><br />
treatment of BPH. Berries from saw palmetto<br />
were first used by the American Indians in the<br />
southeast United States in the early 1700s to<br />
treat testicular atrophy, erectile dysfunction, and<br />
prostate gland swelling or inflammation 1. The<br />
medicinal value of Serenoa repens <strong>for</strong> relief of<br />
prostate gland swelling has been reported since<br />
the 1800s. The mechanism of action of Serenoa<br />
repens has been investigated in several in vitro<br />
or indirect in vivo studies and has not been<br />
definitively defined. The mechanism may include<br />
alteration of cholesterol metabolism,<br />
antioestrogenic, anti-androgenic (including 5areductase<br />
inhibitor activity), anti-inflammatory<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
2 | P a g e
effects, and a decrease in available sex<br />
hormone binding globulin 9±12.<br />
Results of studies a systematic review and<br />
meta-analysis of randomized trials assessed the<br />
existing evidence regarding efficacy and safety<br />
of Serenoa repens in men with symptomatic<br />
BPH 13. Studies were identified through a<br />
search of MEDLINE (1966±1997), EMBASE,<br />
Phytodok, the Cochrane Library, bibliographies<br />
of identified trials and review articles, and<br />
contact with relevant authors and drug<br />
companies. Randomized trials were included if<br />
participants had symptomatic BPH, the<br />
intervention was a preparation of Serenoa<br />
repens alone or in combination with other<br />
phytotherapeutic agents, a control group<br />
received placebo or other pharmacologic<br />
therapies <strong>for</strong> BPH, and the treatment duration<br />
was at least 30 days. Two investigators<br />
independently extracted key data on design<br />
features, subject characteristics, therapy<br />
allocation and outcomes of the studies. A total of<br />
18 studies involving almost 3000 men were<br />
identified and analysed 14±31 (Tables 2±5).<br />
Many studies did not report results in a method<br />
that permitted quantitative meta-analysis.<br />
Sixteen trials were double blinded, 14 were<br />
placebo controlled and four involved Serenoa<br />
repens in combination with other<br />
phytotherapeutic agents. The average study<br />
duration was 9 weeks (range 4±48 weeks) and<br />
the average age of enrollees was 65 years.<br />
Baseline characteristics regarding prostate<br />
volume, urine flow rates and symptom scale<br />
scores were comparable with previous trials<br />
evaluating pharmacologic management of BPH.<br />
The available data indicate that Serenoa repens<br />
(alone or in combination with other<br />
phytotherapeutic agents) improves urinary<br />
symptoms and flow measures (Figs 1±3).<br />
Compared with placebo, saw palmetto improved<br />
urinary symptom scores by 28% and nocturia by<br />
25% (the weighted mean difference .WMD.20:76<br />
times per evening; 95% CI . 21:22 to 20.32; n .<br />
10 studies). Peak urine flow was improved by<br />
24% (WMD . 1:93 ml s21; 95% CI . 0:72 to 3.14,<br />
n . 8 studies), mean urine flow by 28% (2.22 ml<br />
s21; data not shown), and residual urine volume<br />
by 43% (222.05 ml; data not shown). Men taking<br />
Serenoa repens were more likely to report<br />
improvement in urinary symptoms than men<br />
taking placebo (73.6% vs. 50.9%; risk ratio .<br />
1:76). Adverse effects were generally mild and<br />
comparable with placebo. Compared with<br />
finasteride17,30, saw palmetto provided similar<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
responses in urologic symptom scores (0.37<br />
International Prostate Symptom Score (IPSS)<br />
points), nocturia (20.20 times per evening) and<br />
flow measures. Saw palmetto was associated<br />
with a lower rate of erectile dysfunction than<br />
finasteride (1.1% vs. 4.9%; P , 0:001) and<br />
reduced neither prostate size nor prostate<br />
specific antigen (PSA) levels. Critics have stated<br />
that comparing saw palmetto with finasteride<br />
might be showing equivalency to placebo.<br />
However, previous trials and meta-analyses<br />
have demonstrated that finasteride provides<br />
symptomatic improvement in men with prostate<br />
glands .40 g, a size comparable to those<br />
enrolled in this study 32,33.<br />
The treatment effect sizes noted with saw<br />
palmetto were comparable to effects reported<br />
with other pharmacologic agents, such as<br />
finasteride. However, the results should be<br />
viewed cautiously. Studies utilized different<br />
doses and preparations of Serenoa repens<br />
(including combination preparations). The most<br />
extensively investigated preparation of Serenoa<br />
repens is manufactured in France and sold as<br />
Permixon. The most commonly reported dosage<br />
was 160 mg twice per day. Many studies did not<br />
report outcome data in a consistent fashion.<br />
Only three studies reported validated urologic<br />
symptom scales. Trials were of short duration<br />
with only two studies having follow-up of at least<br />
phytotherapy <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
463 6 months’ duration. There<strong>for</strong>e, it is not<br />
known whether Serenoa repens prevents longterm<br />
complications of BPH such as acute urinary<br />
retention or the need <strong>for</strong> surgical intervention.<br />
The only trial comparing Serenoa repens with<br />
alpha-blockers lasted less than 3 weeks, making<br />
a comparison impossible. Finally, it is possible<br />
that study results were not reported if there were<br />
no improvements in symptoms or flow measures<br />
(publication bias). There are two placebocontrolled<br />
studies involving 298 men that were<br />
scheduled <strong>for</strong> completion in 1998. However,<br />
their results have not yet been reported.<br />
Summary Extracts from the saw palmetto plant,<br />
Serenoa repens, provide modest improvement<br />
in urinary symptoms and flow measures.<br />
Compared with finasteride Serenoa repens<br />
produces similar improvements in symptoms<br />
and flow measures, has fewer adverse<br />
treatment effects and costs less. The long-term<br />
safety and efficacy of Serenoa repens and its<br />
ability to prevent complications from BPH are<br />
not known. Standardized preparations are often<br />
not available. Publication of ongoing trials is<br />
3 | P a g e
encouraged and initiation of long term studies<br />
compared with alpha-blockers would be useful.<br />
Hypoxis rooperi (South African star grass,<br />
bsitosterol) Background Phytosterol extracts<br />
derived from the South African star grass,<br />
Hypoxis rooperi, are popular. The resumed<br />
active constituent is b-sitosterol. Beta-sitosterol<br />
contains a mixture of phytosterols, with smaller<br />
amounts of other sterols, bonded with<br />
glucosides 1. Additionally, the quantity of<br />
bsitosterol- bD-glucoside is often reported. The<br />
product is sold under the trade names Harzol or<br />
Azuprostat. Although the mechanism of action of<br />
b-sitosterols is not known it may be related to<br />
cholesterol metabolism or anti-inflammatory<br />
effects (via interference with prostaglandin<br />
metabolism) 1.<br />
Results of studies <strong>for</strong> randomized controlled<br />
trials evaluated b-sitosterol in 519 men with<br />
symptomatic BPH34±37 (Table 3). All were 464<br />
TJ Wilt et al. double-blinded and lasted between<br />
4 and 26 weeks. Three trials used nonglucosidic<br />
b-sitosterols in doses ranging from 30<br />
mg to greater than 120 mg per day 34,35,37.<br />
The other trial utilized a preparation that<br />
contained 100% bsitosteryl- b-D-glucoside (0.15<br />
mg twice a day) 36. The average age of<br />
participants was 65 years. Men had moderately<br />
severe BPH (mean baseline IPSS score . 15:2;<br />
peak urine flow . 10:2ml s21; prostate size . 49<br />
cc.: Beta-sitosterol provided statistically<br />
significant improvements in urinary symptom<br />
scores and flow measures (Figs 4 and 5). In the<br />
two studies reporting the IPSS score, the WMD<br />
compared with placebo was 24.9 points (95% CI<br />
. 26:3 to 23.5, n . 2 studies) (35% improvement).<br />
The WMD <strong>for</strong> peak urine flow was 3.91 ml s21<br />
(45% improvement) and <strong>for</strong> residual volume the<br />
WMD . 228:62 ml (95% CI . 0:91±6:90; n . 4<br />
studies) (29% improvement). Betasitosterol did<br />
not reduce prostate size and the trial using<br />
100% b-sitosteryl- b-D-glucoside (WA184) did<br />
not show improvement in urinary flow rates.<br />
Adverse events were infrequent and mild.<br />
Withdrawal rates were less than 10% and did<br />
not differ from placebo.<br />
An extract from South African star grass, b-<br />
sitosterol, improved urologic symptoms and flow<br />
measures. However, the existing evidence is<br />
limited to trials of short duration, relatively few<br />
patients studied and lack of standardized b-<br />
sitosterol preparations. Their long term<br />
effectiveness, safety and ability to prevent BPH<br />
complications are not known. Secale cereale<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
(rye-grass pollen) Background Rye pollen<br />
extract is prepared from the rye-grass, Secale<br />
cereale. It is used by millions of men worldwide<br />
and is a registered pharmaceutical throughout<br />
Western Europe, Japan, Korea and Argentina<br />
38. In the United States, Cernilton is used as a<br />
nutritional supplement by approximately 5000<br />
men 39. One dose contains 60 mg of Cernitin<br />
T60, a water-soluble pollen extract fraction, and<br />
3 mg of Cernitin GBX, an acetone soluble pollen<br />
extract fraction 38. The acetone-soluble fraction<br />
was found to contain b-sterols 40. In vitro<br />
studies suggest that Cernilton may have antiandrogenic<br />
effects, relax urethral smooth muscle<br />
tone and increase bladder muscle contraction,<br />
or may act on the alpha-adrenergic receptors<br />
and relax the internal and external sphincter<br />
muscles 41±43.<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
467 Results of studies A total of 444 men have<br />
been enrolled in two placebo-controlled .n . 163.<br />
and two comparative trials lasting from 12 to 24<br />
weeks 44±47 (Table 4). Three studies were<br />
double-blinded 44,45,47. The mean age of<br />
participants was 69 years. Differences in the<br />
control agents and methods of reporting results<br />
did not permit all studies to be combined in a<br />
meta-analysis. However, three studies reported<br />
symptom scores or measured symptom<br />
Improvement 45±47. Nocturia was reported in<br />
three studies 44,45,47 and all studies reported<br />
peak urine flow and residual urine volume. Data<br />
from all studies were consistent with<br />
improvement in symptoms and urinary flow.<br />
Cernilton improved ‘self-rated urinary symptoms’<br />
versus placebo and Tadenan, an extract from<br />
Pygeum africanum 46. Almost 70% men taking<br />
Cernilton reported symptom improvement<br />
compared with 29% taking placebo. Obstructive<br />
and irritative symptom scores improved from<br />
baseline by 60% in men taking Cernilton<br />
compared with 40% with Tadenan. Cernilton<br />
reduced nocturia compared with placebo and<br />
Paraprost, a pharmacologic treatment used<br />
primarily in Japan containing 265 mg of L-<br />
glutamic acid, 100 mg of Lalanine and 45 mg of<br />
aminoacetic acid 47. Versus placebo, there was<br />
a two-fold improvement in the percentage of<br />
men reporting improvement in nocturia (63% vs.<br />
31%) 44,45.<br />
Compared with Paraprost, Cernilton reduced<br />
nocturia by 0.40 times per evening. The only<br />
adverse event reported was mild nausea.<br />
Although the results suggest that Cernilton<br />
4 | P a g e
provided modest benefit there are limitations to<br />
the evidence. The longest treatment duration<br />
was 24 weeks. Only one study reported results<br />
from a standardized and validated urologic<br />
symptom scale. While the manufacturer<br />
suggests two to four tablets or capsules daily,<br />
the dosages and standardization of preparation<br />
were not usually reported. The most frequently<br />
reported amount was two Cernilton capsules<br />
three times per day.<br />
Summary<br />
The evidence suggests that an extract from ryegrass<br />
pollen, Cernilton, is well tolerated and<br />
modestly improves urologic symptoms.<br />
However, trials were of short duration, enrolled<br />
relatively few patients, and lacked standard<br />
product preparation. Additionally, there was<br />
infrequent use of validated symptom scale<br />
scores. It does not improve urinary flow<br />
measures and the long-term safety and<br />
effectiveness is not known.<br />
Pygeum africanum (African plum)<br />
Background<br />
Traditionally, the bark of the African plum tree<br />
(Pygeum africanum) was collected and<br />
powdered, then drunk as a tea to improve<br />
genito-urinary symptoms. Purified bark extracts<br />
have been used throughout Europe <strong>for</strong> the past<br />
30 years. The postulated active components<br />
include phytosterols, especially b-sitosterols,<br />
pentacyclic triterpenoids and esters of longchain<br />
fatty alcohols. Pygeum africanum extract<br />
may suppress LUTS by reducing bladder<br />
hyperreactivity, decreasing inflammation, and<br />
protecting against abnormal prostate growth 48.<br />
A 1995 review identified 12 double-blind,<br />
placebo controlled studies involving 717 men<br />
with BPH 46, 49±63 (Table 5). Most studies<br />
used a Pygeum extract under the trade name<br />
Tadenan with doses ranging from 75 to 200 mg<br />
day 21. All studies were at least 16 weeks in<br />
duration. More than half the studies measured<br />
peak urinary flow and all but one measured<br />
urinary frequency. Standardized and validated<br />
symptom scores were not utilized and there was<br />
no pooled estimate of treatment effect size or<br />
adverse events. The majority of studies noted an<br />
improvement in nocturia compared with placebo.<br />
An ongoing double-blind placebo-controlled<br />
study is evaluating Tadenan (100 mg and 400<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
mg) in 750 men with symptomatic BPH. The<br />
primary endpoint is a mean reduction in the<br />
IPSS score between baseline and 6 months.<br />
However, the results have not been reported. In<br />
five small-scale studies involving 183 men, P.<br />
africanum was compared with active drug or<br />
therapy 50,57,63. Two studies involved plant<br />
extracts (sitosterin and extract of Radix urticae<br />
urtae) 50. The results Fig. 5 Effect of b-sitosterol<br />
on peak urine flow vs. placebo 468 TJ Wilt et al.<br />
indicate that Pygeum reduced nocturia more<br />
than comparators in the 3 studies reporting this<br />
endpoint. However, in two of these studies there<br />
were no statistical comparisons. Since the<br />
publication of this review there have been two<br />
additional trials utilizing Pygeum. One was a<br />
study utilizing a combination of Pygeum with<br />
Urtica and is discussed in the section on Urtica<br />
59. The other trial demonstrated that Pygeum<br />
was less effective than Cernilton in improving<br />
‘self-rated urinary symptoms’ 46. Obstructive<br />
and irritative symptom scores improved from<br />
baseline by 60% in men taking Cernilton<br />
compared with 40% in men taking Tadenan.<br />
Summary<br />
Extracts from the African plum tree, Pygeum<br />
africanum may be a useful treatment option <strong>for</strong><br />
BPH. However, inadequacies in the reporting of<br />
outcomes limit the ability to estimate its safety<br />
and efficacy. An ongoing trial should provide<br />
much needed in<strong>for</strong>mation on the short-term<br />
effectiveness and tolerability of Pygeum<br />
africanum.<br />
Urtica dioica (stinging nettle)<br />
Background<br />
Extracts from roots of the stinging nettle are<br />
often used in Germany <strong>for</strong> the treatment of BPH.<br />
The extracts contain a mixture of water- and<br />
alcohol-soluble compounds with extraction<br />
procedures varying from company to company.<br />
Proposed mechanisms of action include<br />
inhibition of <strong>prostatic</strong> growth factor including<br />
blocking the conversion of testosterone to<br />
dihydrostersterone 1. Results of studies There<br />
have been five randomized trials evaluating<br />
stinging nettle. Three of these involved<br />
combinations with other phytotherapeutic agents<br />
(Pygeum and Sabal), making it difficult to<br />
evaluate the efficacy of stinging nettle alone<br />
26,30,59. Furthermore, one of these studies<br />
merely compared two different doses of a<br />
5 | P a g e
combined extract of Urtica and Pygeum59. The<br />
report by Sokeland compared a combination of<br />
Sabal and Urtica (PRO 160/120) extract with<br />
finasteride and placebo30. This trial lasted 12<br />
weeks and evaluated 543 men. Compared with<br />
finasteride there were no differences in IPSS<br />
scores (24.8 vs. 25.8 IPSS points), peak urine<br />
flow or residual urine volume. More adverse<br />
events were associated with finasteride,<br />
including more cases of erectile dysfunction,<br />
diminished ejaculation volume, and headaches.<br />
Compared with placebo, the combination of<br />
Sabal±Urtica (Prostagutt) improved IPSS scores<br />
by 17% (23.5 IPSS points) 26. One placebocontrolled<br />
study lasting 3 months compared a<br />
liquid preparation of stinging nettle with placebo<br />
in 41 men with BPH64. An improvement in IPSS<br />
scores was noted in men taking stinging nettle.<br />
However, because of unacceptable taste this<br />
preparation has been removed from the market.<br />
Another placebo-controlled trial examined the<br />
effectiveness of Urticae extract capsules65.<br />
Although improvements in peak urine flow and<br />
total voided volume were reported, there was no<br />
difference in urologic symptoms. Additionally,<br />
24% of men (6/25) taking Urticae withdrew from<br />
the study; half of them due to unspecified side<br />
effects.<br />
Summary<br />
Evidence from randomized trials suggests<br />
combination preparations of Urticae appear to<br />
provide some benefit <strong>for</strong> treatment of lower<br />
urinary tract symptoms, although stinging nettle<br />
extracts alone do not appear to be beneficial.<br />
Additional randomized controlled trials need to<br />
be conducted be<strong>for</strong>e Urticae can be<br />
recommended as an effective option <strong>for</strong> the<br />
treatment of LUTS.<br />
Curcubita pepo (pumpkin seed)<br />
Results of studies<br />
There has been only one small-scale<br />
randomized trial of short duration that has<br />
evaluated the efficacy of pumpkin seed<br />
extracts16. This study evaluated 55 men, lasted<br />
<strong>for</strong> 12 weeks and utilized a preparation that<br />
included pumpkin seed, Curcubita pepo, and<br />
Sabal serrulata (Curbicin 160 mg three times a<br />
day). Compared with placebo, Curbicin<br />
improved self-rating of urinary symptoms (85%<br />
noted improvement vs. 11% taking placebo) and<br />
nocturia. Residual urine volume was reduced by<br />
<strong>Phytotherapy</strong> <strong>for</strong> <strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong><br />
31% (42.5 cc) compared with only 6.5% (7.6 cc)<br />
with placebo. Because the study utilized a<br />
combination preparation the reported<br />
improvement in urologic symptoms and flow<br />
measures cannot be clearly attributed to<br />
pumpkin seeds.<br />
Summary<br />
There is no convincing evidence that extracts of<br />
pumpkin seed alone improve urologic symptoms<br />
or flow measures. They may provide<br />
improvement in urinary symptoms and flow<br />
measures when used in combination with Sabal<br />
serrulata. Randomized controlled trials need to<br />
be conducted. Recommendations and<br />
conclusions Should physicians recommend plant<br />
extracts <strong>for</strong> treatment of BPH Despite their<br />
popularity and the existence of over 40<br />
randomized controlled trials involving nearly<br />
5000 men, the available data do not yet provide<br />
clear evidence of efficacy <strong>for</strong> most<br />
phytotherapeutic products. Extracts of saw<br />
palmetto (Serenoa repens) (alone or in<br />
combination with other phytotherapeutic<br />
products) have the strongest evidence <strong>for</strong><br />
efficacy and tolerability. They appear to be a<br />
useful option <strong>for</strong> improving lower urinary tract<br />
symptoms and flow measures. Rye-grass pollen<br />
(Secale cereale) and South African star grass<br />
(Hypoxis rooperi, b-sitosterol) also appear to<br />
improve symptoms and are well tolerated.<br />
However, the evidence is <strong>Phytotherapy</strong> <strong>for</strong><br />
<strong>benign</strong> <strong>prostatic</strong> <strong>hyperplasia</strong> 469 less strong <strong>for</strong><br />
these products. African plum tree bark (Pygeum<br />
africanum) has been studied extensively but<br />
inadequate reporting of outcomes limits the<br />
ability to conclusively recommend it. There is no<br />
convincing evidence supporting the use of<br />
pumpkin seed (Curcubita pepo) or stinging nettle<br />
(Urtica dioica) extracts alone <strong>for</strong> treatment of<br />
BPH. They may be effective in combination with<br />
other phytotherapeutic products. The<br />
widespread use of phytotherapy attests to the<br />
popularity of plant extracts <strong>for</strong> treatment of BPH<br />
symptoms. They cost less and are better<br />
tolerated, at least in the shortterm, than either<br />
alpha-blockers or finasteride. However, if the<br />
primary goal is to reduce symptoms, alphablockers<br />
such as doxazosin, tamsulosin,<br />
alfuzosin or terazosin seem to be a better choice<br />
than finasteride and probably phytotherapy.<br />
Additionally, plant extracts have not yet been<br />
demonstrated to reduce complications from BPH<br />
or the need <strong>for</strong> surgical intervention in<br />
comparison with interventions such as<br />
6 | P a g e
finasteride33. The Committee on Other Medical<br />
Therapies of the Fourth International<br />
Consultation on BPH concluded that: most plant<br />
extract preparations have different components;<br />
it is not known what mechanisms of action<br />
demonstrated in vitro might be responsible <strong>for</strong><br />
clinical effects; short-term randomized studies<br />
suggest clinical efficacy <strong>for</strong> some preparations;<br />
and studies were usually inadequate due to the<br />
methodology utilized, small numbers and short<br />
duration of study. Of greatest importance is the<br />
completion of additional high quality studies of<br />
long duration to fully evaluate the efficacy and<br />
safety of phytotherapeutic products <strong>for</strong> treatment<br />
of BPH6. Until completion of these studies<br />
and/or regulation of these products the lack of<br />
universal definitions, practices, and standards<br />
within the supplement industry place the onus<br />
on the physician to judge product quality and<br />
efficacy. Manufacturers/companies of plant<br />
extracts often use different extraction processes.<br />
There is no evidence that the extract from one<br />
manufacturer is equivalent to that of another.<br />
Additionally, since the active ingredient(s) are<br />
not known, it is possible that one product might<br />
have clinical efficacy while another does not.<br />
Each company's product must be tested to<br />
evaluate clinical efficacy and bioactivity. The<br />
following recommendations have been made <strong>for</strong><br />
assessing quality measures (these do not<br />
directly address clinical efficacy or safety) in<br />
selecting high-quality and reliable preparations<br />
of phytotherapeutic products manufactured in<br />
the United States66. 1. The manufacturer tests<br />
raw ingredients <strong>for</strong> purity and potency prior to<br />
inclusion in a product. 2. The product is<br />
manufactured in a pharmaceutically licensed<br />
facility registered with the Food and Drug<br />
Administration. 3. The product's ingredients<br />
meet the applicable United States<br />
Pharmacopoeia (USP) standards. 4. All finished<br />
products are analyzed <strong>for</strong> purity and potency<br />
following production by an independent<br />
laboratory using established methods to ensure<br />
that the product meets label claims and is of<br />
good quality. In some cases, this in<strong>for</strong>mation<br />
can be found on product labeling. All reputable<br />
manufacturers will keep certificates of laboratory<br />
results <strong>for</strong> each finished batch of product on file.<br />
These should be available to physicians and<br />
pharmacists on request.<br />
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